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Individualized Stabilization CriteriaeDriven

Ranibizumab versus Laser in Branch Retinal

Vein Occlusion

Six-Month Results of BRIGHTER

Ramin Tadayoni, MD, PhD,1 Sebastian M. Wald st ein, MD,2 Francesco Boscia, MD,3 Heinrich Ger ding, MD,4,5

Ian Pearce, FRCOphth,6 Siegfried Priglinger, MD,7 Andreas Wenzel, PhD,8 Elizabeth Barnes, PhD,8

Margarita Gekkieva, MD,8 Stefan Pilz, PhD,9 Jordi Monés, MD, PhD,10 on behalf of the BRIGHTER study group*

Purpose: To compare the 6-month ef cacy and safety prole of an individualized stabilization criteriaedrivenpro re nata (PRN) regimen of ranibizumab 0.5 mg with or without laser versus laser alone in patients with visualimpairment due to macular edema secondary to branch retinal vein occlusion (BRVO).

Design: A 24-month, prospective, open-label, randomized, active-controlled, multicenter, phase IIIb study. Participants: A total of 455 patients. Methods: Eligible patients were randomized 2:2:1 to receive ranibizumab (n ¼ 183), ranibizumab with laser

(n ¼ 180), or laser only (n ¼ 92). Patients treated with ranibizumab with or without laser received a minimum of 3initial monthly ranibizumab injections until visual acuity (VA) stabilization, and VA-based PRN dosing thereafter. Inthe ranibizumab with laser and laser-only groups, laser was given at the investigator ’s discretion at a minimuminterval of 4 months and if VA was

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adjunctive laser has ef cacy similar to the mont hly dosingregimen that was assessed in the BRAVO study.2

The BRAVO study was the rst prospective 12-month,randomized, sham-controlled, multicenter study that demon-strated the effectiveness of ranibizumab in managing patientswith macular edema secondary to BRVO. The improvementsin best-corrected visual acuity (BCVA) and central fovealthickness (CFT) observed with a monthly dosing of ranibi-

zumab 0.5 mg in the rst 6 months (baseline to month 5; at month 6, mean change in BCVA: þ18.3 letter s [primary endpoint] and mean change in CFT: 345.2 mm)2 were largelymaintained with a PRN dosing regimen and monthlymonitoring until month 12 (mean change in BCVA: þ18.3letters and mean change in CFT: 347.4 mm).4

The HORIZON study (cohort 2; ClinicalTrials.govidentier: NCT00379795) was a 1-year, open-label exten-sion of the BRAVO and Ranibizumab for the Treatment of Macular Edema after Central Retinal Vein OcclUslonStudy: Evaluation of Ef cacy and Safety (CRUISE) studies.In this study, it was observed that the gains in BCVAachieved at the end of 12 months in the BRAVO and

CRUISE studies were maintained for an additional 12months with a PRN dosing regimen and with less frequent monitoring. A total of 60.3% of patients gained 15 lettersin the HORIZON study (similar to 60.3% at month 12 in theBRAVO study).5,6

The BRIGHTER study is designed to address thefollowing questions to aid physicians in optimizing treat-ment for patients with BRVO: (1) provide long-term data onthe ef cacy and safety of the individualized visual acuity(VA) stabilization criteria edriven PRN dosing regimen of ranibizumab 0.5 mg in a broad patient population withBRVO, including those with macular ischemia; and (2) theimpact of adjunct laser treatment on BCVA outcome and thenumber of ranibizumab injections required. Here, we report

the 6-month primary and main secondary outcomes from the24-month BRIGHTER study (Group members of this studyare cited in Appendix 1, available at www.aaojournal.org).

Methods

Study Design

The BRIGHTER study was a 24-month, phase IIIb, randomized,open-label, active-controlled, 3-arm, multicenter study assessingthe ef cacy and safety prole of an individualized stabilizationcriteria edriven PRN dosing regimen of ranibizumab 0.5 mg withor without laser versus laser alone in patients with visual impair-

ment due to macular edema secondary to BRVO. The study isbeing conducted across 17 countries worldwide (Appendix 2,available at www.aaojournal.org). The study started in May 2012and was completed in 2015. The rst 6 months of theBRIGHTER study were conducted from May 2012 andNovember 2015 and that included recruitment and all the other steps.

The study was conducted in accordance with the Declaration of Helsinki, and the study protocol was reviewed and approved by anindependent ethics committee or institutional review board at eachcontributing center. Patients provided written informed consent before entering the study. The study is registered with Clinical-trials.gov as NCT01599650.

Patients

The study population consisted of patients aged 18 years withvisual impairment due to macular edema secondary to BRVO. Thekey inclusion criteria included a BCVA letter score at screeningand baseline between 73 and 19 Early Treatment Diabetic Reti-nopathy Study (ETDRS) letters, inclusive (approximate Snellenequivalent of 20/40 and 20/400).

The key exclusion criteria included stroke or myocardial

infarction 160/ >100 mmHg) at screening or baseline; periocular or ocular infection or inammation at screening or baseline; intra-vitreal anti-VEGF injections 3 months before baseline and sys-temic anti-VEGF injections 6 months before baseline;uncontrolled glaucoma (intraocular pressure 30 mmHg onmedication or according to the investigator ’s judgment) at the timeof screening or baseline or diagnosed within 6 months beforebaseline; laser photocoagulation for macular edema 4 monthsbefore baseline; intraocular or periocular corticosteroid use 3months before baseline; and known hypersensitivity to ranibizu-mab or any component of the ranibizumab formulation or uo-rescein. In addition, pregnant or nursing women were excludedfrom the study (inclusion and exclusion criteria are listed inAppendix 3, available at www.aaojournal.org).

Randomization and Treatment

At enrollment, eligible patients were randomized in a 2:2:1 ratio toreceive ranibizumab 0.5 mg, ranibizumab 0.5 mg with laser, or laser alone. The randomization list was generated using a validatedsystem that automates the random assignment of treatment arms torandomization numbers in the specied ratio. The randomizationwas balanced across the sites. Although this was an open-labelstudy, the vision examiner who assessed the BCVA outcomeswas masked and not allowed to perform any additional study tasksthat would have unmasked him or her to study treatment.

In the ranibizumab with or without laser groups, ranibizumab0.5 mg was administered as recommended in t he European Union

Summary of Product Characteristics (2012).

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Patients receivedranibizumab 0.5 mg injections on day 1, followed by initialmonthly injections until the study eye’s VA was stable (based onthe judgment of the investigator) for at least 3 consecutivemonths; by design, at least 3 initial injections were required8

(Fig 1, available at www.aaojournal.org). Once VA was stable,ranibizumab treatment was temporarily discontinued at theinvestigator ’s discretion. In the ranibizumab with laser and laser-only groups, patients were treated with laser as soon as indicatedby the investigator. When ranibizumab and laser were to beadministered on the same day to the study eye, the laser treatment was applied 30 minutes before the ranibizumabinjection.

Maintenance and Re-treatment

All patients were monitored monthly for VA and disease activity. If there was a loss of VA due to disease activity as judged by theinvestigator, monthly ranibizumab injections were again adminis-tered to the patients in the ranibizumab with or without laser groupsuntil stability was achieved for 3 consecutive months; this requiredat least 2 consecutive injections.8 In the ranibizumab with laser andlaser-only groups, patients were re-treated with laser at the in-vestigator ’s discretion at minimum intervals of 4 months in thepresence of macular edema secondary to BRVO, as long as theBCVA was

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this 6-month analysis. If both eyes were eligible at screeningand baseline, the study eye was selected on the basis of theinvestigator ’s discretion. The other eye (labeled the fellow eye)was allowed to receive ranibizumab treatment within the studyaccording to the local label, according to the investigator ’s judg-ment. The use of rescue medication was not permitted in this study.

Study Objectives

The primary objective of this 24-month study was to demonstratethe superior ef cacy of ranibizumab with or without laser whencompared with laser alone over 6 months. This was assessed bythe mean change in BCVA from baseline at month 6 in patientstreated with ranibizumab with or without laser versus laser alone(primary end point). The secondary objectives were (1) to comparethe ef cacy of ranibizumab with or without laser versus laser alonefor (a) the mean average change in BCVA from baseline to month1 through month 6, (b) the proportion of patients with a BCVAimprovement of 10/ 15/ 30 letters at month 6, (c) the propor-tion of patients attaining a BCVA of 73 letters at month 6, and (d)the mean change in central reading center (CRC)eassessed centralsubeld thickness (CSFT) from baseline to month 6; (2) to assessthe treatment exposure of ranibizumab and laser; and (3) to eval-uate the safety prole of ranibizumab over 6 months. An explor-atory objective was to evaluate the ef cacy of the 3 treatments inrelation to the following baseline characteristics: presence of macular ischemia (present and absent); BCVA (39, 40e59, and60 letters); and duration of BRVO (12 and >12 months), byassessing the mean average change in BCVA from month 1through month 6. An additional exploratory objective was to assessthe change from baseline to month 6 of the CRC-assessed categoricoptical coherence tomography (OCT) parameters (CSFT catego-rized, CFT categorized, visible intraretinal cystoid uid [IRF], andsubretinal uid [SRF]). Denitions of these quantitative and cate-goric spectral-domain OCT parameters are listed in Appendix 4(available at www.aaojournal.org).

Efcacy and Safety Assessments

Study assessments were performed at screening, baseline (day 1),day 8, and monthly visits.

Best-Corrected Visual Acuity. The BCVA was assessed bycertied vision examiners at every study visit using ETDRS VAtesting charts at an initial testing distance of 4 m. If it was not possible to perform a subjective refraction or VA testing at 4 m because VA was too poor for the patient to read 4 letters on theETDRS chart at this distance, the refraction or VA testing wereattempted at 1 m.

Optical Coherence Tomography. Optical coherence tomogra-phy was performed by certied site personnel at each visit usingspectral-domain OCT equipment (e.g., Heidelberg Spectralis[Heidelberg Engineering, Heidelberg, Germany]; Cirrus HD-OCT[Carl Zeiss, Oberkochen, Germany]; 3D-OCT 1000 or 3D-OCT

2000 [Topcon, Tokyo, Japan]; and Nidek RS-3000 [Nidek, Fre-mont, CA]). The same equipment was used for assessment throughout the study. The investigator or designated study staff evaluated the images according to the standard practice andrecorded the required variables in the clinical database. The imagesalso were assessed by a CRC to ensure a standardized evaluation of the CSFT (the average retinal thickness of the circular area with a 1-mm diameter around the foveal center) and to capture the pres-ence or absence of qualitative parameters (i.e., CFT, IRF, andSRF). Raw data of the images were evaluated in validated CRCsoftware. The inner and outer retinal boundaries were segmented at predened standardized locations to ensure standardization acrossthe used spectral-domain OCT instruments.

Fluorescein Angiography and Color Fundus Photo-graphy. Fluorescein angiography (in conjunction with 7-eld color fundus photography) images were evaluated by the investigator for the presence or absence of macular edema, capillary leakage, andnonperfusion within the 3-mm perifoveal subeld.

The CRC used a standardized grading system to assess macula r ischemia on uorescein angiography, as reported previously.

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Macular ischemia was characterized by the extent of retinalcapillary loss (presence or absence of nonperfusion) in the

ETDRS-like grid center subeld, as well as inner and outer sub-elds (Appendix 5, available at www.aaojournal.org). We denedmacular ischemia as present if capillary loss was scored as mild,moderate, severe, or completely destroyed in 1 location of thecenter, inner, or outer subelds of the grid (Appendix 5, availableat www.aaojournal.org). In this article we present only the ef cacyresults based on CRC-assessed macular ischemia. The investigator used all images to decide the need for re-treatment.

Treatment Exposure. Information on the number of ranibizu-mab injections or laser administration over 6 months was collected.

Safety Assessments. Safety assessments included type, fre-quency, and severity of adverse events (AEs) and serious AEs(SAEs) over 6 months.

Statistical AnalysisBy assuming a standard deviation (SD) of 14 letters for the change(normal distributed) in BCVA from baseline at month 6, based on a randomization ratio of 2:2:1 and estimating a dropout rate of approximately 10%, a sample size of 180 randomized patients eachin the ranibizumab and ranibizumab þ laser arms and 90 patients inthe laser-only arm was considered. This sample size had a power of 90.5% to detect a treatment difference of 7 or more letters at a 1-sided a level of 0.0125 for an unstratied analysis (based onunstratied ManneWhitney test using PASS 2002 software;NCSS, LLC, Kaysville, UT).

The primary and secondary ef cacy outcomes were analyzedwithin the full analysis set (FAS) using the last observation carriedforward approach. The FAS included all randomized patients who

had 1 post-baseline assessment for BCVA in the study eye andwho received 1 administration of study treatment, except patientsrandomized to laser monotherapy, who were included even without receiving study treatment.

The hypothesis of the superiority of ranibizumab withor without laser compared with laser alone was tested in parallelaccording to the Hochberg procedure, controlling the overall 1-sided a level at 0.025. The primary and secondary ef cacy out-comes related to the mean change in BCVA from baseline wereassessed on the basis of pairwise analysis of variance models that included factors for treatment and baseline BCVA category(BCVA 39, 40e59, and 60 letters). The least squares meansand standard error were calculated for each of the treatment groups,along with the 2 pairwise differences of their 95% condence in-terval (CI). The number and proportion of patients with BCVA

letter gain or loss from baseline were analyzed by a stratiedCochraneManteleHaenszel test with stratication based on base-line BCVA (39, 40e59, 60 letters). The CRC-assessed CSFTwas summarized descriptively and analyzed via pairwise analysisof variance models including factors for treatment, OCT machinetype, and categorized baseline BCVA (39, 40e59, and 60letters). The CRC-assessed categoric OCT parameters were sum-marized using FAS observed data for the study eye.

All safety analyses were descriptive and performed on thesafety set that included all patients who had 1 post-baselinesafety assessment and received 1 administration of the studytreatment, except for patients randomized to laser monotherapy,who were included even without receiving the study treatment.

Tadayoni et al Ranibizumab versus Laser in BRVO

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Statistical analysis was performed using SAS software version 9.1(SAS Institute, Inc., Cary, NC).

Results

Patient Disposition

A total of 455 patients were randomized to receive ranibizumab

(183 patients), ranibizumab with laser (180 patients), or laser alone (92 patients) (Fig 2). A total of 424 patients (93.2%)completed the rst 6 months of the study (174 in theranibizumab group, 170 in the ranibizumab with laser group, and80 in the laser-only group) (Fig 2). Overall, withdrawal of consent (n ¼ 12) and AEs (n ¼ 8) were the most commonreasons for study discontinuation. The FAS included 180 patientsreceiving ranibizumab, 178 patients receiving ranibizumab withlaser, and 90 patients receiving laser monotherapy. The safetyanalysis set included 180 patients receiving ranibizumab, 183patients receiving ranibizumab with laser (there were 3 patientsin the laser monotherapy group who received ranibizumab and 1patient in the ranibizumab monotherapy group who receivedlaser treatment, resulting in percentages >100%), and 88 patientsreceiving laser monotherapy.

The baseline demographic characteristics were comparableamong the 3 treatment groups (Table 1). Overall, the mean (SD)age of the patients was 66.3 (10.30) years, the proportion of male and female patients was similar (49.7% vs. 50.3%), and themajority (94.9%) of patients were white (Table 1). The baselinemean (SD) BCVA was 57.7 (12.88) letters, and the majority of patients (52.5%) had a BCVA letter score 60 at baseline(Table 1). The mean (SD) duration of BRVO was 9.9 (21.28)months, and the median duration was 2.9 months ( Table 1). TheBRVO subtype was BRVO in 89.0% of patients and hemi-retinal

vein occlusion in 10.5% of patients (Table 1). Overall, 24.8% of patients in the randomized set had ischemic perfusion type at baseline, according to the investigator ’s assessment. Theproportion of patients with macular ischemia at baseline basedon CRC assessment was similar between treatment groups(48.1% of patients in the ranibizumab group, 40.0% of patientsin the ranibizumab with laser group, and 44.6% of patients in thelaser only group). There were 31.1%, 37.8%, and 31.5% of patients with macular ischemia as “cannot grade” based on CRC

assessment in the ranibizumab, ranibizumab with laser, and laser-only groups, respectively.

Efcacy

Best-Corrected Visual Acuity. Ranibizumab with or without laser was superior to laser alone in improving mean (SD) BCVA from baseline at month 6 (14.8 [10.70] and 14.8 [11.13] vs. 6.0 [14.27]letters, respectively; both P < 0.0001); thus, the primary end point was met (Fig 3). Likewise, mean (SD) average gain in BCVA from month 1 through month 6 was higher in the ranibizumab (13.2[9.60] letters) and ranibizumab with laser groups (13.2 [9.89]letters) compared with the laser-only group (4.8 [11.69] letters);estimated least squares means (standard error; 95% CI) treatment difference versus laser were 9.4 letters [1.21; 7.0e11.7] (P <0.0001) for ranibizumab and 8.2 letters [1.24; 5.8e10.6] (P <0.0001) for ranibizumab with laser. In the ranibizumab andranibizumab with laser groups, a rapid and clinically relevant improvement in mean BCVA was observed at month 1, whichcontinued up to month 3 and slightly increased from month 3until the last assessment time point at month 6 (Fig 3).

At month 6, a larger proportion of patients gained 10/ 15/ 30letters with ranibizumab with or without laser versus laser alone(Fig 4). At month 6, 65.6% and 54.5% of patients attained a BCVAscore of 73 letters with ranibizumab and ranibizumab with laser,

Figure 2. Patient disposition (randomized set). Randomized set consisted of all patients who were randomized. Because patients with multiple reasons are

counted once for each reason of nonrandomization, percentages may add up to more than 100%. AE ¼ adverse event; BRVO ¼ branch retinal vein

occlusion.

Ophthalmology Volume -, Number -, Month 2016

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respectively, compared with 31.1% of patients with laser only(estimated treatment difference vs. laser, 34.44% [95% CI,

22.6e46.3] for ranibizumab and 23.38% [95% CI, 11.3e35.4] for ranibizumab with laser; both P 12months) was 16.4/8.4 letters in the ranibizumab group, 15.0/11.5letters in the ranibizumab with laser group, and 5.9/7.1 letters in thelaser-only group (Fig 7).

Anatomic Outcomes. At month 6, there was a greater reduc-tion in CRC-assessed mean CSFT in patients treated with

Table 1. Baseline Demographics, Disease, and Ocular Characteristics (Randomized Set*)

Demographic Variable Ranibizumab 0.5 mg (n[ 183)Ranibizumab 0.5 mg D laser

(n [ 180) Laser monotherapy (n [ 92) Total (N [ 455)

Age, yrsn 183 180 92 455Mean (SD) 64.7 (10.34) 67.3 (10.41) 67.7 (9.67) 66.3 (10.30)

Sex, n (%)Male 93 (50.8) 96 (53.3) 37 (40.2) 226 (49.7)

Female 90 (49.2) 84 (46.7) 55 (59.8) 229 (50.3)Predominant race, n (%)

White 171 (93.4) 172 (95.6) 89 (96.7) 432 (94.9)Black 1 (0.5) 1 (0.6) 0 2 (0.4)Asian 5 (2.7) 3 (1.7) 3 (3.3) 11 (2.4)

Native American 1 (0.5) 0 0 1 (0.2)Other 5 (2.7) 4 (2.2) 0 9 (2.0)

VA (letters)n 181 179 91 451Mean (SD) 59.5 (11.77) 56.6 (13.16) 56.5 (14.13) 57.7 (12.88)

VA stratication group,n (%)

39 letters 16 (8.7) 22 (12.2) 11 (12.0) 49 (10.8)40e59 letters 55 (30.1) 72 (40.0) 36 (39.1) 163 (35.8)

60 letters 110 (60.1) 85 (47.2) 44 (47.8) 239 (52.5)

Missing 2 (1.1) 1 (0.6) 1 (1.1) 4 (0.9)IOP, mmHg

n 181 179 91 451Mean (SD) 15.1 (2.49) 15.4 (3.02) 15.2 (2.88) 15.2 (2.79)

Subtype of BRVO, n (%)Hemi 19 (10.4) 19 (10.6) 10 (10.9) 48 (10.5)Branch 164 (89.6) 159 (88.3) 82 (89.1) 405 (89.0)Missing 0 2 (1.1) 0 2 (0.4)

Perfusion type,y n (%)Ischemic 47 (25.7) 42 (23.3) 24 (26.1) 113 (24.8)

Nonischemic 135 (73.8) 134 (74.4) 66 (71.7) 336 (73.8)Missing 1 (0.5) 4 (2.2) 1 (1.1) 6 (1.3)

Duration of BRVO, monthsn 181 179 90 450Mean (SD) 10.3 (19.63) 9.2 (19.92) 10.5 (26.66) 9.9 (21.28)Median 3.1 3.3 2.0 2.9

Duration of BRVO, n (%)

12 mos 145 (79.2) 145 (80.6) 76 (82.6) 366 (80.4)>12 mos 36 (19.7) 34 (18.9) 14 (15.2) 84 (18.5)Missing 2 (1.1) 1 (0.6) 2 (2.2) 5 (1.1)

BRVO ¼ branch retinal vein occlusion; IOP ¼ intraocular pressure; SD ¼ standard deviation; VA ¼ visual acuity.Percentages are based on the total number of patients in the randomized set.Baseline was dened as the last available nonmissing value collected just before the start of treatment.*Consisted of all patients who were randomized.yPerfusion type as indicated by the investigator.


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ranibizumab with or without laser compared with patients treatedwith laser alone (223.3/240.1 vs. 89.8 mm; P < 0.0001) (Fig 8).At month 6, the proportion of patients with CSFT and CFT 450mm increased from baseline in all treatment groups; the proportionwas higher in the ranibizumab with or without laser groups thanin the laser-only group (Table 2A, available at www.aaojournal.org). The proportion of patients with visibleIRF and SRF decreased from baseline in all treatment groups;the proportion was higher in the ranibizumab with or without laser groups than in the laser-only group (Table 2B, available at www.aaojournal.org).

Treatment Exposure

Ranibizumab Injections. The mean number of ranibizumab injections over 6 months was 4.8 and 4.5 in the ranibizumab andranibizumab with laser groups, respectively (Fig 9).

Laser Treatments. The mean number of laser treatments given

up to 6 months was 0.0, 0.8, and 1.2 in the ranibizumab, ranibi-zumab with laser, and laser-only groups, respectively (Fig 10).

Safety

Serious Adverse Events. Ocular SAEs were reported in the studyeye in 2 patients in the ranibizumab with laser group during the6 months of the study: macular hole in 1 patient (not considered bythe investigator to be related to the study drug or ocular injection)and ocular ischemic syndrome (considered by the investigator tobe related to the study drug) in the other patient (Table 3,available at www.aaojournal.org). Nonocular SAEs were reportedin 10, 7, and 2 patients in the ranibizumab, ranibizumab withlaser, and laser-only groups, respectively (Table 3, available at

www.aaojournal.org). One patient died of acute respiratoryfailure in the ranibizumab group (Table 3, available at www.aaojournal.org). The death was not considered by theinvestigator to be related to the study treatment or ocular injection.

Adverse Events. Ocular AEs in the study eye were reported in28.3%, 37.2%, and 13.6% of patients in the ranibizumab, ranibi-zumab with laser, and laser-only groups, respectively (Table 4).Conjunctival hemorrhage and eye pain were the most commonlyreported ocular AEs in patients receiving ranibizumab or ranibizumab with laser (Table 4).

The incidence of nonocular AEs was similar among the 3groups (Table 4). Hypertension was the most common nonocular AE reported in all 3 groups. Ocular and nonocular AEs

Figure 3. Mean change in best-corrected visual acuity (BCVA) from baseline to month 6 (full analysis set [FAS]). The FAS consisted of all randomized

patients who had 1 postbaseline assessment for BCVA in the study eye and who received 1 administration of study treatment, except patients randomized

to laser monotherapy, who were included even without receiving study treatment. yBoth ranibizumab and ranibizumab þ laser versus laser alone, pairwise

analysis of variance. SE ¼ standard error.

Figure 4. Categorized gain in best-corrected visual acuity (BCVA) at

month 6 (full analysis set [FAS]). The FAS consisted of all randomized

patients who had 1 post-baseline assessment for BCVA in the study eye

and who received 1 administration of study treatment, except patients

randomized to laser monotherapy, who were included even without

receiving study treatment.


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suspected to be related to the study drug treatment during the rst 6months of the study are listed in Table 5 (available at www.aaojournal.org). Treatment- or ocular injectionerelatedocular AEs were reported in 17.8% of patients in the ranibizu-mab group and 23.5% of patients in the ranibizumab with laser group. Nonocular AEs occurred in 1.7% of patients in the ranibi-zumab group, 2.2% of patients in the ranibizumab with laser group,and none in the laser-only group. Ocular and nonocular AEsleading to study drug discontinuation are listed in Table 6(available at www.aaojournal.org).

There were no reports of retinal neovascularization during the6-month period of this study. Retinal hemorrhages werereported in

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recommended dosing regimen. The 6-month primary anal-ysis did not show additional benets with the ranibizumabplus laser combination over ranibizumab monotherapy,either in BCVA outcomes or in the required number of in-

jections, which could be due to the short duration assess-ment of this 24-month study.

The patients in this study required a mean of 4.8 rani-bizumab 0.5 mg injections (of which 3 were mandatory per protocol) over 6 months to achieve mean BCVA gainsof þ14.8 letters. In real-life studies with ranibizumab inpatients with neovascular age-related macular degenerationor central retinal vein occlusion, the mean number of in-

jections over a 1-year period have been reported to rangebetween 4 and 5 in the retrospective analysis part of theLUMINOUS study and 4.4 in the VERO study.13,14

At month 6, the proportion of patients with a gain of 15 letters in the BRAVO study with monthly ranibizu-mab treatment was higher than in the BRIGHTER study

with stabilization criteria edriven PRN ranibizumab treat-ment (61.1% vs. 45.0%). The mean change in BCVA from baseline at month 6 was numerically higher in the BRAVOstudy (þ18.3 lett ers) compared with the BRIGHTER study(þ14.8 letters),4 which could be due to the differences inpatient baseline characteristics in the 2 studies. Patients in

the BRIGHTER study had a higher mean baseline BCVAscore (59.5 letters in BRIGHTER vs. 53.0 letters inBRAVO) and a longer mean duration of BRVO (9.9months in BRIGHTER vs. 3.3 months in BRAVO).However, the absolute mean BCVA at month 6 washigher in the BRIGHTER study than in the BRAVO study(74.3 vs. 71.3 letters) (Fig 11), with a lower mean number of injections (4.8 vs. 5.7, respectively). The functionaloutcomes observed at month 6 of the BRIGHTER studywere similar to those of the VIBRANT study (assessinga ibercept for the treatment of BRVO15), in which 52.7%of patients gained 15 letters and mean BCVA change

Figure 6. Mean change in best-corrected visual acuity (BCVA) from baseline to month 6 by baseline BCVA (full analysis set [FAS]). FAS consisted of all

randomized patients who had 1 postbaseline assessment for BCVA in the study eye and who received 1 administration of study treatment, except patients

randomized to laser monotherapy, who were included even without receiving study treatment. D ¼ day.


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from baseline was 17.0 letters, and provide further support to the ndings of VIBRANT that suppression of VEGFover 6 months provides superior visual outcomescompared with treatment with focal/grid laser alone.However, any comparisons between BRIGHTER andprevious studies of patients with BRVO need to beinterpreted with caution considering the differences in thepatient populations, study designs, and anti-VEGF treat-ment regimens investigated.

The exploratory subgroup analysis performed in the

BRIGHTER study showed that the individualized stabi-lization criteria edriven PRN dosing regimen of ranibi-zumab was effective in patients with BRVO irrespectiveof the baseline VA, disease duration, or presence of macular ischemia. The mean change in BCVA from baseline at month 6 with ranibizumab treatment wassimilar between patients with ischemia and patientswithout ischemia. The difference in the percentage of patients at baseline with CRC-assessed macular ischemia and investigator-assessed nonperfusion could be relatedto the individual assessment method used and needs to beinvestigated in future studies. In addition, the impact of

the severity and location of ischemia on ef cacy warrantsfurther investigation.

Several studies of anti-VEGF for other indications haveshown baseline VA to be an importa nt predictor of VAoutcomes at later time points.16e19 Likewise, inBRIGHTER, the mean gain in BCVA at month 6 washigher in patients with lower baseline VA scores, whereasthe absolute nal BCVA values were lower in those withpoor baseline VA. In addition, BCVA gain at month 6 washigher in patients with a shorter duration of disease, sug-

gesting that early treatment initiation with ranibizumabirrespective of the BCVA scores may provide better VAgains in patients with BRVO. This is supported by thereduced visual gains observed in the sham arm of theBRAVO study due to delayed treatment initiation(switching into PRN treatment after 6 months).Similar ndings have been reported in the sham arms of studies of ranibizumab for other indications,20 as well as inobservational studies of patients with age-related macular degeneration.21,22

No new safety concerns were identied with ranibizumabwith or without laser treatment. The single death reported in

Figure 7. Mean change in best-corrected visual acuity (BCVA) from baseline to month 6 by duration of branch retinal vein occlusion (full analysis set

[FAS]). The FAS consisted of all randomized patients who had 1 postbaseline assessment for BCVA in the study eye and who received 1 administration

of study treatment, except patients randomized to laser monotherapy, who were included even without receiving study treatment. D ¼ day; M ¼ month.


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the ranibizumab group was not related to the study drug.There were no reports of endophthalmitis, neovascular glaucoma, or iris neovascularization.

This is a 6-month primary analysis of a study. This short period was insuf cient to provide conclusive evidence of the

benets of combining laser with ranibizumab, especiallybecause laser administration occurred at a minimum interval of 4 months. Theexploratory analysisof the effect of ranibizumabtreatment focused on macular ischemia. This study explicitly

Figure 8. Mean change in central subeld foveal thickness (CSFT) from baseline to month 6 (full analysis set [FAS]). The FAS consisted of all randomized

patients who had 1 postbaseline assessment for BCVA in the study eye and who received 1 administration of study treatment, except patients randomized

to laser monotherapy, who were included even without receiving study treatment. yBoth ranibizumab and ranibizumab þ laser versus laser alone, pairwise

analysis of variance. SE ¼ standard error.

Figure 9. Ranibizumab treatment exposure up to month 6 (safety set). Safety set consisted of all patients who had 1 postbaseline safety assessment and

received 1 administration of study treatment, except patients randomized to laser monotherapy, who were included even without receiving study

treatment. The total number of injections per patient is calculated, and these per-patient values are summarized. SD ¼ standard deviation.


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excluded patients with previous treatments within 3months like other randomized studies to facilitate comparison.

The 24-month results of the BRIGHTER study are ex-pected to provide additional information on the long-term ef cacy and safety of the individualized stabilizationcriteria edriven dosing of ranibizumab 0.5 mg, as well as thelong-term benets of combining ranibizumab with laser.The individualized stabilization criteria edriven dosingregimen used in this study led to an average reduction of 1injection over the course of 6 months in comparison with

monthly dosing. The second-year data from this study willprovide further information on the benets of fewer visitscombined with the individualized dosing regimen.

In conclusion, the 6-month data from the BRIGHTERstudy demonstrate that an individualized ranibizumabtreatment with or without laser is superior to laser mono-therapy in signicantly improving BCVA in patients withBRVO. The exploratory analysis showed similar BCVA

Figure 10. Laser treatment exposure up to month 3 (safety set). Safety set consisted of all patients who had 1 postbaseline safety assessment and received

1 administration of study treatment, except patients randomized to laser monotherapy, who were included even without receiving study treatment.

Multiple sessions for the initial laser treatment are counted as 1 application. The total number of laser applications per patient is calculated, and these per-

patient values are summarized. SD ¼ standard deviation.

Table 4. Ocular (Study Eye) and Nonocular Adverse EventsRegardless of Study Drug Relationship (Safety Set*)

Preferred Termn (%)

Ranibizumab0.5 mg

(n [ 180)

Ranibizumab0.5 mg D Laser

(n [ 183)

LaserMonotherapy

(n [ 88)

Ocular AEs,total

51 (28.3) 68 (37.2) 12 (13.6)

Conjunctivalhemorrhage

11 (6.1) 12 (6.6) 0 (0)

Eye pain 8 (4.4) 10 (5.5) 0 (0)Vitreous

detachment6 (3.3) 4 (2.2) 0 (0)

IOP increased 5 (2.8) 8 (4.4) 0 (0)Vitreous oaters 3 (1.7) 5 (2.7) 2 (2.3)

Nonocular AEs,total

60 (33.3) 52 (28.4) 27 (30.7)

Hypertension 11 (6.1) 10 (5.5) 5 (5.7)

Nasopharyngitis 6 (3.3) 5 (2.7) 3 (3.4)Headache 4 (2.2) 6 (3.3) 3 (3.4)

AE ¼ adverse event; IOP ¼ intraocular pressure.Preferred terms that occurred in 2% of the safety set are included in thissummary. Preferred terms are sorted in descending frequency, as reported inthe ranibizumab 0.5 mg column. A patient with multiple occurrences of anAE under 1 treatment is counted only once in the AE category for thattreatment.*Consisted of all patients who had 1 postbaseline safety assessment andreceived 1 administration of study treatment, except patients randomized tolaser monotherapy, who were included even without receiving studytreatment.

Figure 11. Mean best-corrected visual acuity (BCVA) from baseline to

month 6 in BRIGHTER and BRAVO. yBCVA was assessed on day 7 in

BRAVO and day 8 in BRIGHTER. D ¼ day.


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gains between patients with macular ischemia and patientswithout macular ischemia, and suggests that better VA gainsmay be obtained at 6 months with early treatment initiationirrespective of the baseline BCVA scores. Overall, therewere no safety concerns other than those reported in theprevious studies.

Acknowledgments. The authors thank Sabyasachi Ghosh andLakshmi Venkatraman (Scientic Services Practice- PLS, NovartisHealthcare Pvt. Ltd., Hyderabad, India) for medical writing andeditorial assistance in the development of this article.

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Footnotes and Financial Disclosures

Originally received: October 13, 2015.

Final revision: February 16, 2016.

Accepted: February 17, 2016.

Available online: ---. Manuscript no. 2015-1780.

1Ophthalmology Department, Hôpital Lariboisière, AP-HP, Université

Paris 7 - Sorbonne Paris Cité, Paris, France.

2Vienna Reading Center, Department of Ophthalmology, Medical Uni-

versity of Vienna, Vienna, Austria.

3Clinica Oculistica, University of Sassari, Sassari, Italy.

4Department of Retinology, Klinik Pallas, Olten, Switzerland.

5Department of Ophthalmology, University of Münster, Münster,

Germany.6

St Paul’s Eye Unit, Royal Liverpool University Hospital, Liverpool,

United Kingdom.7

Department of Ophthalmology, Ludwig-Maximilians-University, Munich,

Germany.8

Novartis Pharma AG, Basel, Switzerland.9

Munich Re, Munich, Germany.


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10Institut de la Màcula, Centro Médico Teknon, and Barcelona Macula

Foundation, Barcelona, Spain.

Presented at: the World Ophthalmology Congress, April 2e6, 2014, Tokyo,

Japan; Association for Research in Vision and Ophthalmology (ARVO)

Annual Meeting, May 4e8, 2014, Orlando, Florida; 14th EURETINA

Congress, September 11e14, 2014, London, United Kingdom; American

Academy of Ophthalmology, October 18e21, 2014, Chicago, Illinois; 14th

European School for Advanced Studies in Ophthalmology Retina Acad-

emy, November 13e15, 2014, Istanbul, Turkey; 46th Annual Scientic

Congress of the Royal Australian and New Zealand College of Ophthal-

mologists, November 22e26, 2014, Brisbane, Australia; 30th Asia-Pacic

Academy of Ophthalmology Congress, April 1e4, 2015, Guangzhou,

China; Asia-ARVO, February 16e19, 2015, Yokohama, Japan; and

ARVO, May 1e5, 2015, Denver, Colorado.

*Group members are listed in Appendix 1 (available at www.aaojournal.

org).

Financial Disclosure(s):

The author(s) have made the following disclosure(s): R.T.: Board

member Alcon, Switzerland; Novartis, Switzerland; Allergan, USA;

Bausch & Lomb, USA; Alimera, USA; Bayer, Germany; FCI-Zeiss,

France; Roche, Switzerland, ThromboGenics, Belgium, Zeiss, Germany;

Consultant Allergan, USA; Alcon, Switzerland; Novartis, Switzerland;

Bausch & Lomb, USA; FCI-Zeiss, France; ThromboGenics, Belgium;

Lecture fees Alcon, USA; Bausch & Lomb, USA; Novartis, Switzerland;Allergan, USA; Bayer, Germany; Alimera, USA; Zeiss, Germany; Educa-

tional presentation fees Bausch & Lomb, USA; Novartis, Switzerland;

Zeiss, Germany; Sony, Japan; Alcon, Switzerland; Allergan, USA; Meeting

expenses Novartis, Switzerland; Alcon, Switzerland; Allergan, USA;

Bausch & Lomb, USA; Bayer, Germany; Alimera, USA.

S.M.W.: Consultant Bayer HealthCare, Novartis; Grant support

Christian Doppler Research Society; Travel support e Novartis.

F.B.: Consultant Novartis, Bayer, Alcon, ThromboGenics, Alimera,

Pfenex, Allergan; Lecture honoraria Novartis and Bayer.

H.G.: Board member Novartis, Switzerland, Bayer, Switzerland;

Consultant Novartis Switzerland; Novartis, Germany, Bayer,

Switzerland; Bayer, Germany; Allergan, Switzerland; ESBAtech,

Switzerland; Lecture honoraria Novartis, Switzerland; Novartis, Ger-

many; Bayer, Switzerland; Bayer, Germany, Heidelberg Engineering,Germany.

I.P.: Consultant/advisor e Novartis; Lecture fees Novartis, Allergan,

Heidelberg Engineering.

A.W., E.B., and M.G.: Employees Novartis Pharma AG, Basel,

Switzerland.

S.P.: Employee Novartis Pharma AG, Basel, Switzerland, at the time of

development of the article; currently employed with Munich Re.

J.M.: Consultant/advisor Novartis, Alcon, Allergan, Bayer, Ophthotech,

Notal Vision; Grant support Novartis, Alcon, Bayer, Ophthotech; Lecture

fees Novartis, Allergan, Ophthotech; Options e

Ophthotech and NotalVision.

This multicenter study was funded and managed by Novartis and is

registered with www.clinicaltrials.gov (NCT01599650). Proprietary or

commercial disclosures can be found after the references.

Author Contributions:

Conception and design: Tadayoni, Waldstein, Boscia, Gerding, Pearce,

Priglinger, Wenzel, Barnes, Gekkieva, Monés

Data collection: Tadayoni, Waldstein, Boscia, Gerding, Pearce, Priglinger,

Wenzel, Barnes, Gekkieva, Monés, BRIGHTER study group

Analysis and interpretation: Tadayoni, Waldstein, Boscia, Gerding, Pearce,

Priglinger, Wenzel, Barnes, Gekkieva, Monés, BRIGHTER study group

Obtained funding: Not applicable

Overall responsibility: Tadayoni, Waldstein, Boscia, Gerding, Pearce,

Priglinger, Wenzel, Barnes, Gekkieva, Monés, BRIGHTER study group

Abbreviations and Acronyms:

AE ¼ adverse event; BCVA ¼ best-corrected visual acuity;

BRAVO ¼ BRAnch Retinal Vein Occlusion: Evaluation of Ef cacy and

Safety; BRVO ¼ branch retinal vein occlusion; CFT ¼ central foveal

thickness; CI ¼ condence interval; CRC ¼ central reading center;

CRUISE ¼ Ranibizumab for the Treatment of Macular Edema after

Central Retinal Vein OcclUslon Study: Evaluation of Ef cacy and Safety;

CSFT ¼ central subeld thickness; ETDRS ¼ Early Treatment Diabetic

Retinopathy Study; FAS ¼ full analysis set; IRF ¼ intraretinal cystoid

uid; OCT ¼ optical coherence tomography; PRN ¼ pro re nata;

SAE ¼ serious adverse event; SD ¼ standard deviation; SRF ¼ subretinal

uid; VA ¼ visual acuity; VEGF ¼ vascular endothelial growth factor.

Correspondence:

Ramin Tadayoni, MD, PhD, Ophthalmology Department, Hôpital Lar-iboisière, 2, rue Ambroise Paré, Paris 75010, France. E-mail: ramin.

[email protected].


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